Pharmaceutical composition for treating multiple sclerosis

ABSTRACT

Use of a compound of the general formula I and/or a pharmaceutically acceptable salt thereof as active ingredient for the preparation of a pharmaceutical composition for the treatment of multiple sclerosis in humans:  
                 
wherein 
         X represents NCH 3 , O or S.    A represents an unsubstituted C 1-4  alkylene or a substituted C 1-4  alkylene that is mono- or poly-substituted with substituents independently selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3  und CH(CH 3 ) 2 ,    M represents H; benzoyl; unsubstituted C 1-12  alkanoyl; substituted C 1-12  alkanoyl that is mono- or poly-substituted with substituents independently selected from CH 3 , CH 2 CH 3 , F and Cl; unsubstituted C 1-12  alkyl; or substituted C 1-12  alkyl that is mono- or poly-substituted with substituents independently selected from CH 3 , CH 2 CH 3 , F and Cl;    R represents CH 3 , CH 2 CH 3  or NR 1 R 2 , wherein R 1  and R 2  independently represent H, CH 3  or CH 2 CH 3 , and    Y 1 , Y 2  and Y 3  are independently selected from H, CH 3 , CH 2 CH 3 , F and Cl.

The present invention relates to the use of organic compounds for thepreparation of a pharmaceutical composition for the treatment ofmultiple sclerosis in humans.

BACKGROUND OF THE INVENTION

Multiple sclerosis (encephalomyelitis disseminata) (MS) is one of themost frequent nervous diseases. Its cause is not yet known. Up to thepresent day, there is no causal therapy at hand, but many attempts havebeen made to alleviate the effects of the disease. The treatment,limited in time, of the aggravation of MS by attacks with cortisonepreparations has been found thereby to be helpful.

In spite of intense treatment attempts for relapse prophylaxis of MSusing immuno-suppressing medicaments, such as Imurek®, and for theimmuno-modulation with β-interferone preparations, such as Betaferon®,no convincing breakthrough has yet been obtained to hold up theprogression of MS.

In northern Europe, Canada and the northern states of the United States,MS is the most frequent progressing disease of the central nervoussystem. The age when the illness strikes is between 20 and 40 years,women are to a slight extent more often affected than men.

The chronic inflammatory reaction of MS is characterized by complexinteractions between cellular and humoral elements of the immune system,adhesion molecules on endothelial cells and imflammatory cells as wellas a series of low-molecular mediators of inflammation. Among themediators of inflammation, cytokins play animportant role.

The symptoms of MS are variegated and comprise in the prodromal stageinter alia pseudo-neurasthenic symptoms, cerebral nerve failures(retrobulbar neuritis, ophthalmoplegia, syllabism), spasticity,cerebellum symptoms, paraesthesia, bladder and rectum dysfunction;euphoria, the development of a subsequent dementia, is possible.

Despite intense research, the aetiology of the chronic inflammatorydevelopment has remained unclear. Essential pathogenetic mechanismscould be elucidated in the last two decades by pathologic-anatomic andimmunologic studies in patients as well as by experimental work with ananimal model of the MS, the experimental allergic encephalomyelitis(EAE). It is assumed that auto-immune reactions to myelin antigensmediated by T-cells play an important role.

Since the cause of MS still remains unknown up to the present day, thetreatment of this disease has always proven to be problematic. Thecontroversial situation of MS therapy (Bauer, H. I.: “Nervenarzt”, 54,1983, 400 to 405) has been revealed in more than 100 attempts attreatment which have been carried out, at least at times, in medicine,including unconventional methods and methods by outsiders.

Some authors have postulated an infectious cause of MS and onehypothesis assumes that viruses could play a significant role. When aviral infection was assumed, the administered therapeutic agents, inparticular amantadin or methisazon, did not show convincing results. Theuse of interferon has also been discussed in many cases, however, theresults of the treatment were not convincing as regards the progress ofthe disease.

Other principles of treatment are based on metabolic theories. Theassumptions of possible protein metabolism disturbances are based on thepresence of a number of biogenetic amines which could not be found inhealthy human beings.

The metabolism hypothesis is based on trials with highly unsaturatedfatty acids (omega fatty acids), since a lower MS prevalence is observedwhen there is a higher consumption of vegetable oil or fish.

Other studies are based on thrombocyte aggregation, which issignificantly increased in MS patients during the attacks of thedisease. This has led to treatment tests with aggregation-inhibitingtherapeutic substances.

Finally, the attempt was made to use cortico-steroids and immunesuppressors in therapeutic methods which could attenuate in the acuteearly phase the intensity and duration of the corresponding phases ofthe attacks. Due to the great adverse effects of the cortico-steroids,ACTH, etc., an application is only possible which is limited in time,although this application cannot prevent further attacks. At present,the pulse therapy with cortisone preparations during the attack hasbecome accepted.

Apart from the above-mentioned therapies, a number of unconventionalmethods has been tried, including acupuncture, special diets,mega-vitamin therapies, etc. In addition, 15 to 20 years ago the oxygenoverpressure therapy was propagated (B. Fischer, New England J. Med.,303, 1983, 181 to 186).

The difficulties of MS research and therapy are, on the one hand, due tothe fact that the causes and the elicitor of the disease are unknown.There is an animal model for testing medicaments, the experimentalallergic encephalomyelitis (EAE), however, the results thereof cannotautomatically be transferred to humans.

In Acta Neurol. Scand. 75, 1987, 361-363 (Neu, et al.), the release ofleucotrienes from neutrophils and from suspensions of thrombocytes andneutrophils in reaction to Ionophor A23187 was measured. Based on theresults of this scientific study, it was postulated that the release ofthe sulfidopeptid leucotriene could be involved in the perivenous plaqueformation in MS. It is further stated therein that the suppression ofthe leucotriene. synthesis by medicaments might be a promisingtherapeutic concept if these results could be confirmed for a greaternumber of MS patients and in comparisons with other neurologicaldiseases in EAE trials. This literature source allows the conclusion tobe drawn that the scientific observations have not been made with arepresentative number of patients and that therefore conclusions are notpossible. Although comparisons with other neurological diseases havebeen proposed, the exact genesis of these diseases was not given.Further, tests on EAE animals were considered necessary, although it isknown that the results of these test systems can only be transferred toMS patients to a limited extert. This was, in the end, again confirmede.g. for the antimetabolite azothioprin (Imurek®), which showedpromising indications in the E animal test, but was not convincing inthe treatment of MS patients.

Further, the attempt was made to exert influence on the progression ofMS via a pharmacological blockade with leucotriene biosynthesisinhibitors and leucotriene receptor antagonists. In the animal model itwas possible to suppress the inflammatory reactions of MS via apharmacological blockade of leucotriene C₄ with chemical leucotrieneinhibitors and sulphosalacines. These sulphosalazines (Azulfidine®),which were successful in the animal model, were tested on MS patients ina clinical study. In the first 18 months of the treatment withazulfidine in a double blind study carried out in the United States andCanada, an exceptionally beneficial effect could be proven. However,three years after the end of the study this effect could no longer beproven. Here, the problem of the limited transferability of the resultsof test systems on animals to MS patients was again to be observed.

A further study also tried to use a leucotriene inhibiting substance. Inthis study, the Boswellia acid (Boswellia serrata) was tested, acomponent of the incense resin, which is predominantly used for treatingrheumatoid polyarthritis, bronchial asthma and colitis ulcerosa. A goodleucotriene inhibiting effect was observed in vitro. No success could,however, be obtained with the animal experimental study of the Boswelliaacid. A treatment attempt with MS patents was therefore superfluous.

In summary, it has been shown that no conclusive method is to be foundin the literature, in, which specific active ingredients could be usedin a successful therapy of MS.

OBJECT OF THE INVENTION

It is therefore an object of the invention to provide an activeingredient for the preparation of a pharmaceutical composition for thetreatment of MS in humans.

INVENTION

The object of the present invention is solved by the use of a compoundof the general formula I and/or a pharmaceutically acceptable saltthereof as active ingredient for the preparation of a pharmaceuticalcomposition for the treatment of multiple sclerosis in humars:

-   -   wherein    -   X represents KCH₃, O or S,    -   A represents an unsubstituted C₁₋₄ alkylene or a substituted        C₁₋₄ alkylene that is mono- or poly-substituted with        substituents independently selected from CH₃, CH₂CH₃, CH₂CH₂CH₃        und CH(CH₃)₂,    -   M represents H; benzoyl; unsubstituted C₁₋₁₂ alkanoyl;        substituted C₁₋₁₂ alkanoyl that is mono- or poly-substituted        with substituents independently selected from CH₃, CH₂CH₃, F and        Cl; unsubstituted C₁₋₁₂ alkyl; or substituted C₁₋₁₂ alkyl that        is mono- or poly-substituted with substituents independently        selected from CH₃, CH₂CH₃, F and Cl;    -   R represents CH₃, CH₂CH₃ or NR¹R², wherein R¹ and R²        independently represent H, CH₃ or CH₂CH₃, and    -   Y¹, Y² and Y³ are independently selected from H, CH₃, CH₂CH₃, F        and Cl.

It was surprisingly found that the frequency of the attacks and thechronic progression decreased when a compound of the general formula Iand/or a pharmaceutically acceptable salt and/or a hydrate thereof wasadministered to patients ill with multiple sclerosis. This result isunexpected since the causes, the symptoms and the behaviour of MS and ofthe persons ill therewith are either unknown or very complex.

The compounds of formula I according to the invention preferably usedinclude those compounds wherein, independently or in one or severalcombinations,

-   -   wherein    -   M represents H,    -   at least two of Y¹, Y² and Y³ represent H,    -   A represents CH₂ or CHCH₃, and    -   X represents S.

The active ingredient used according to the invention can be used assuch and/or in the form of pharmaceutically acceptable salts thereof.

If sterical isomers, such as optical isomers or conformation isomers, orhydrates and complexes of the compounds of the invention exist, thepresent invention includes each and all of them. The compounds of thepresent invention and the methods for preparing the same are disclosede.g. in U.S. Pat. No. 4 873 259.

Examples of the compounds of the general formula I used in accordancewith the present invention are

-   -   N-hydroxy-N-(1-benzo[b]thien-2-ylethyl) acetamide,    -   1-(1-Benzo[b]thien-2-ylethyl)-1-hydroxy urea,    -   N-hydroxy-N-(1-benzo[b]thien-2-ylethyl)-N′-methyl urea,    -   N-hydroxy-N-(1-benzo[b]thien-2-ylethyl)-N′,N′-dimethyl urea,    -   N-hydroxy-N-benzo[b]thien-2-yl;methyl urea,    -   N-hydroxy-N-benzo[b]thien-2-ylmethyl-N′-methyl urea,    -   N-hydroxy-N-benzo[b]thien-2-ylmethyl-N′,N′-dimethyl urea,    -   N-hydroxy-N-(1-benzo[b]thien-3-ylethyl) acetamide,    -   N-hydroxy-N-(1-benzo[b]thien-3-ylethyl) urea,    -   N-hydroxy-N-[1-(3-methylbenzo[b]thien-2-yl)-ethyl]urea,    -   N-hydroxy-N-(1-benzo[b]fur-2-ylethyl) acetamide,    -   N-hydroxy-N-(1-benzo[b]fur-2-ylethyl) urea,    -   N-hydroxy-N-[1-(1-methylindol-3-yl)-ethyl]acetamide,    -   N-hydroxy-N-[1-(1-methylindol-3-yl)-ethyl]urea,    -   N-hydroxy-N-[1-(1-methylindol-3-yl)-ethyl]-N′-methyl urea,    -   N-hydroxy-N-[1-(5-chlorbenzo[b]fur-2-yl)-ethyl]urea,    -   N-hydroxy-N-[1-(5-fluorbenzo[b]thien-2-yl)-ethyl]urea.

The use according to the invention of:

-   -   N-hydroxy-N-(1-benzo[b]thien-2-ylethyl) acetamide,    -   1-(1-benzo[b]thien-2-ylethyl)-1-hydroxy urea,    -   N-hydroxy-N-(1-benzo[b]thien-2-ylethyl)-N′-methyl urea, or    -   N-hydroxy-N-(1-benzo[b]thien-2-ylethyl)-N′,N′-dimethyl urea is        preferred.

Particularly preferred is the use according to the invention of1-(1-benzo[b]thien-2-ylethyl)-1-hydroxy urea, in the following alsodesignated zileuton:

Zileuton can either be used as a racemic mixture of the R(+)- and S(−)enantiomers or in the form of its pure enantiomers. The use of theracemate is preferred.

Usually, the active ingredient is used in an amount of 0.001 to 2.0 mg,preferably in an amount of 0.01 to 2.0 mg, more preferably in an amountof 0.1 to 1.0 mg, and most preferably in an amount of 600 mg per dose.The administration is performed once to five times daily, preferablyfour times daily.

Therapeutic Forms of Administration

The preparation of pharmaceutical compositions having a content of acompound of the general formula I and/or a pharmaceutically acceptablesalt thereof or their use in the utilization according to the inventionis carried out in the common manner by means of conventionalpharmaceutic-technological methods. Advantageous is e.g. the processingtogether with suitable, pharmaceutically acceptable adjuvants and/orcarrier substances in the pharmaceutical forms which are suitable forthe various indications and types of application. It could also be anadvantage if the medicament comprises further active ingredients.

One important systemic form of application is the peroral administrationin the form of tablets, hard or soft gelatine capsules, dragees, powder,pellets, micro-capsules, oblong compressed tablets, granulates, chewabletablets, sucking tablets, chewing gum, sachets or globuli.

As adjuvants for the preparation of pharmaceutical compositions forperoral admiristration, the following are, for example, used:double-side adhesives and lubricants and separating agents, dispersionagents, such as e.g. flame-dispersing silicon dioxide, disintegrants,such as e.g. various kinds of starch, PVP, cellulose ester as agranulating agent, such as e.g. wax-like and/or polymeric materials usedon the basis of Eudragit®, cellulose or Cremophor®.

Antioxidants, sweetening agents, such as e.g. saccharose, xylite odermannitol, taste correctors, flavouring agents, preservatives, colouringagents, buffer substances, topical application agents, such as e..g.microcrystalline cellulose, starch and starch hydrolisates (e.g.Celutab®), lactose, polyethylene glycoles, polyvinyl pyrrolidone anddi-calcium phosphate, lubricants, fillers, such as e.g. lactose orstarch, binders in the form of lactose, types of starch, such as wheator corn or rice starch, cellulose derivatives, such as e.g. methylcellulose, hydroxypropyl cellulose or silica, talcum, stearates, such ase.g. magnesium stearate, aluminium stearate, calcium stearate, talc,siliconized talc, stearine acid, cetyl alcohol, hydrated fats, may alsobe used.

The common emulsions, gels, ointments, creams or mixed-phase oramphipathic emulsion systems (oil/water-water/oil mixed phase) as wellas liposomes and transferosomes can also be mentioned for a conventionalapplication to the skin.

For example, as adjuvants or carriers sodium alginate is suited as agelatinizing agent for the preparation of a suitable base, or cellulosederivatives, such as e.g. guar or xanthane gum, an organic gelatinizingagents, such as e.g. aluminium hydroxides or bentorites (so-calledthixotropic gelatinizing agents), polyacrylic acid derivatives, such ase.g. Carbopol®, polyvinyl pyrrolidone, microcrystalline cellulose orcarboxymethyl cellulose. Further, amphipatic low- and high-molecularcompounds such as phospholipids are to be considered. The gels can bepresent either as hydrogels on a water basis or as hydrophobicorganogels, e.g. on the basis of mixtures of low- and high-molecularparaffin hydrocarbons and vaseline.

Anionic, cationic or neutral tensides, e.g. alkali soaps, metal soaps,amine soaps, sulfurated and sulfonated compounds, invert soaps, higherfatty alcohols, partial fatty acid esters of sorbitan andpolyoxyethylene sorbitan, wool wax, lanolin or other synthetic productsmay be used as emulgators for the preparation of the oil/water and/orwater/oil emulsions.

The hydrophilic organogels can be prepared e.g. on the basis ofhigh-molecular polyethylene glycols. These gel-like forms can be washedoff. Vaseline, natural or synthetic waxes, fatty acids, fatty alcohols,fatty acid esters, e.g. as mono-, di- or triglycerides, paraffin oil orvegetable oils, hardened castor oil or coconut oil, lard, syntheticfats, e.g. on the basis of capryl, capron, laurate and stearic acid, ortriglyceride mixtures such as Miglycol®, are used as lipids in the formof fat-like and/or oil-like and/or wax-like components for thepreparation of ointments, creams or emulsions.

Osmotically effective acids and bases, e.g. hydrochloric acid, citricacid, sodium hydroxide solution, caustic potash solution, sodiumhydrogen carbonate, further buffer systems, such as e.g. citrate,phosphate, tris-buffer or triethanolamine may be used for the adjustmentof the pH value.

Preservatives, e.g. methyl or propylbenzoate (parabene) or sorbic acidmay also be added in order to increase the stability.

Pastes, powders or solutions can be mentioned as further topicallyapplicable forms. As the consistency-forming base, the pastes frequentlycontain lyophilic and hydrophilic adjuvants having a very highproportion of solids. In order to increase the dispersing effect, theflowability and lubricating property and to avoid forming agglomerates,the powders or topically applicable powders may contain e.g. types ofstarch, such as wheat starch or rice starch, flame dispersing silicondioxide or silica, which also serve as diluents.

In particular, plasters may be produced as transdermal systems which areable to release the active ingredient in a controlled manner over alonger or shorter period of time on the basis of various layers and/ormixtures of suitable adjuvants and carriers. For the purpose of animproved and/or accelerated penetration, those substances are used inthe preparation of such transdermal systems, which enhance the membranepermeation, or permeation promoters, such as e.g. oil acid, Arzone®,adipin acid derivatives, ethanol, urea, propylglycol, together withsuitable adjuvants and carriers, such as solvents, polymer components,e.g. on the basis of Eutragit®.

Further, injections may also be administered. They are prepared eitherin the form of ampoules or also as so-called injections ready for use,e.g. as prepared syringes or disposable syringes and, in addition tothis, for a repeated extraction, also in septum flasks. The injectionsmay be administered in the form of a subcutaneous (s.c.), intramuscular(i.m.), intravenous (i.v.) or intracutaneous (i.c.) application. Therespective appropriate forms of injections may be prepared in particularas solutions, crystal suspensions, nano-particular or colloid-dispersingsystems, such as e.g. hydrosols.

The preparations to be injected may also be prepared as concentrateswhich may be adjusted with aqueous isotonic diluents to the desiredactive ingredient dosage. They may further be produced as powders, suchas e.g. lyophylisates, which are then, preferably prior to application,dissolved with suitable diluents or are dispersed.

As adjuvants and carriers when preparing injectable preparations aquasterilisata may be used as well as substances which have an influence onthe pH value, e.g. organic and inorganic acids and bases as well assalts thereof, buffer substances for adjusting the pH value,isotonisation agents, such as e.g. sodium chloride, sodium hydrogencarbonate, glucose and fructose, tensides or surfactants and emulgators,such as e.g. partial fatty acid esters of polyoxyethylene sorbitans(Tween®), or e.g. fatty acid esters of polyoxyethylene (Cremophor®),fatty oils, such as e.g. peanut oil, soybean oil and castor oil,synthetic fatty acid esters, such as e.g. ethyloleate, isopropylmyristate and neutral oil (Miglycol®), as well as polymeric adjuvants,such as e.g. gelatine, dextran, polyvinyl pyrrolidone, additives oforganic solvents increasing solvability, such as e.g. propylene glycol,ethanol, N,N-dimethyl acetamide, propylene glycol or completing agents,such as e.g. citrates and urea, preservatives, such as e.g. benzene acidhydroxypropyl and methyl ester, benzene alcohol, antioxidants, such ase.g. sodium sulfite and stabilizers, such as e.g. EDTA.

The skilled person may easily recognize and prepare the respectivesuitable forms of the medicament in accordance with the rules andregulations for prescriptions and the procedures on the basis ofpharmaceutical-physical principles.

The use of zileuton in the form von Zyflo™Filmtab® tablets has proven tobe particularly advantageous. This substance is indicated in adults andchildren of 12 and older for the prophylaxis of asthma and the treatmentof chronic asthma and is authorized in the United States for thisindication. The use of zileuton for the preparation of Zyflo™Filmtab®tablets, as are distributed by the Abbott laboratories in the UnitedStates for the treatment of multiple sclerosis in humans, is alsoincluded in the present invention.

Experimental Part

15 patients having clinically active MS were treated with zileuton in atreatment trial. 15 MS patients without this treatment served as acontrol. One tablet of Zyflo™Filmtab® was administered to each fourtimes a day. The study had a duration of three years. As compared withthe 15 MS patients without this treatment, the frequency of attacks andthe chronic progression significantly decreased in the MS patientstreated with zileuton.

In order to prove the effect of the therapy, nuclear magnetic resonancespectroscopies of the brain were carried out every six months using thecontrast agent Magnevist®, so that the floridity or acuteness of thecentres (florides) of inflammation could be objectified. No new or acutecentres absorbing the contrast agent could be determined in the MSpatients treated with zileuton

1. Use of a compound of the general formula I and/or a pharmaceuticallyacceptable salt thereof as active ingredient for the preparation of apharmaceutical composition for the treatment of multiple sclerosis inhumans:

wherein X represents NCH₃, O or S, A represents an unsubstituted C₁₋₄alkylene or a substituted C₁₋₄ alkylene that is mono- orpoly-substituted with substituents independently selected from CH₃,CH₂CH₃, CH₂ CH₂CH₃ and CH(CH₃)₂, M represents H; benzoyl; unsubstitutedC₁₋₁₂ alkanoyl; substituted C₁₋₁₂ alkanoyl that is mono-orpoly-substituted with substitutents independently selected from alkylenethat is mono- or poly-substituted with substituents independentlyselected from CH₃, CH₂CH₃, F and Cl; unsubstituted C₁₋₁₂ alkyl; orsubstituted C₁₋₁₂ alkyl that is mono- or poly-substituted withsubstitutents independently selected from CH₃, CH₂CH₃, F and Cl; Rrepresents CH₃, CH₂CH₃, or NR¹R², wherein R¹ and R² independentlyrepresent H, CH₃, or CH₂CH₃, and Y¹, Y² and Y³ are independentlyselected from H, CH₃, CH₂CH₃, F and Cl.
 2. Use according to claim 1,wherein M represents H.
 3. Use according to claim 1, wherein at least ofY¹, Y² or Y³ represent H.
 4. Use according to claim 1, wherein Arepresents CH₂ or CHCH₃.
 5. Use according to claim 1, wherein Xrepresents S.
 6. Use according to claim 1, wherein the compound of thegeneral formula I is selected from: N-hydroxy-N-(l-benzo[b]thien-2-ylethyl)acetamide, 1-(1-benzo[b]thien-2-ylethyl)-1-hydroxy urea,N-hydroxy-N-(1-benzo[b]thien-2-ylethyl)-N′-methyl urea,N-hydroxy-N-(1-benzo[b]thien-2-ylethyl)-N′,N′-dimethyl urea,N-hydroxy-N-l-benzo[b]thien-2-ylmethyl urea,N-hydroxy-N-1-benzo[b]thien-2-ylmethyl-N′-methyl urea,N-hydroxy-N-1-benzo[b]thien-2-ylmethyl-N′,N′-dimethyl urea,N-hydroxy-N-(1-benzo [b]thien-3-ylethyl) acetamide, N-hydroxy-N-(1-benzo[b]thien-3-ylethyl) urea,N-hydroxy-N-[1-(3-methylbenzo[b]thien-2-yl)-ethyl]urea, andN-hydroxy-N-[1-(5-fluorobenzo[b]thien-2-yl)-ethyl]urea.
 7. Use accordingto claim 1, wherein the pharmaceutical composition additionallycomprises one or more pharmaceutically acceptable carriers and/or one ormore toxicologically safe adjuvants.
 8. Use according to claim 1,wherein the pharmaceutical composition comprises further activeingredients.
 9. Use according to claim 1, wherein the pharmaceuticalcomposition is prepared in one of the following forms: in the form of aninhalation therapeutic agent, in the form of a transdermal therapeuticsystem, in the form of a gastro-intestinal therapeutic system, astablet, ointment, suspension, emulsion, balm, plaster, or dosageaerosol.
 10. Use according to claim 1, wherein the concentration of theactive ingredient amounts to 0.001 to 2.0 mg per dose.
 11. Use accordingto claim 10, wherein the concentration of the active ingredient amountsto 0.1 to 2.0 mg per dose.
 12. Use according to claim 10, wherein theconcentration of the active ingredient amounts to 0.1 to 1.0 mg perdose.
 13. Use according to claim 1, wherein the medicament is preparedfor one to five daily dosages.